The type of immune response that is elicited upon infection of a host with a pathogen is critical in determining whether the pathogen is eradicated or whether chronic infection ensues. The inability thus far to intervene immunologically to abrogate many chronic diseases such as HIV, malaria, TB, schistosomiasis for example, highlights the need for a deeper understanding of the immune response to infectious challenge. Successful protective effector responses to intracellular pathogens such as parasites, bacteria and viruses are initiated by cells of the innate immune response which produce effector cytokines such as TNF, IL-12 or IFN-alpha which stimulate antigen-specific Th1 cells producing IFN-gamma, and CD8+ T cytotoxic T cell (CTL). Humoral immune responses also offer protection against pathogens, however rapid mutations in the organisms and/or the lack of immunizing regimens which lead to long-term protection, impede successful vaccination. Host mutations in cytokine signalling pathways and signalling pathways downstream of pattern recognition receptors on host immune cells, result in profound susceptibility to a number of pathogens. Furthermore, many organisms such as Leishmania, Schistosoma or Mycobacteria inhibit protective immune responses via the induction of suppressive cytokines, whereas influenza has developed molecular mechanisms to interfere directly with signalling pathways important for the induction of the host antiviral response. Major reasons why we have failed to-date in eliminating human pathogens are: successful strategies of immunoevasion developed by pathogens to dampen an immune response, and conversely pathogen induced immunopathologies complicate infections. Furthermore, the emergence and reemergence of many infectious pathogens throughout human history, the difficulty in producing effective vaccines to protect against numerous pathogens, and the inability to intervene immunologically to abrogate many chronic infectious diseases such as HIV, malaria, TB, and schistosomiasis for example, highlights the need for a deeper understanding of the immune response to infectious challenge. The proposed Keystone Meeting will result in cross-fertilization of knowledge gained from animal models of infectious disease to human immune responses to such important pathogens and is critical to advance the treatment and prevention of devastating pathogens.